The binding of selectins, a group of cell surface lectins, to carbohydrate ligands like sialyl-Lewis.sup.X (sLe.sup.X) and sialyl-Lewis.sup.A (sLe.sup.A), is mediating the attraction of several groups of leukocytes to areas of inflammation (review: S. R. Watson, Adhes. Recept. Ther. Targets 1996, 61-73, Editor A. M. Horton, CRC, Boca Raton, Fla.). This has stimulated research to investigate the use of carbohydrates and their mimetics as potential drugs to prevent the adhesion and subsequent migration of leukocytes to the affected tissues in several acute and chronic inflammatory diseases.
The major natural ligands of the selectins are the sialyl Lewis.sup.X (sLe.sup.X) and sialyl-Lewis.sup.A (sLe.sup.A) determinants found on the termini of various glycolipids and glycoproteins. Synthetic variations of the functional groups of sLe.sup.X and sLe.sup.A have led to a more detailed knowledge about structure-activity-relationships of the functional groups involved in binding to selectins. FIG. 1 shows the essential structural requirements in sLe.sup.X depicted in bold. The structure of sLe.sup.A is derived from sLe.sup.X by interchange of the NeuAc-(.alpha.2,3)-Gal(.beta.1,4)- and Fuc(.alpha.1,3)-residues on the GlcNAc moiety.
It is known that the acid function present in the sialic acid moiety is crucial and can be replaced, i.e. by sulfate groups. Furthermore, the fucose and some of the galactose hydroxyl groups are essential. The hydroxyl groups and the acetamido group in the sialic acid moiety are believed to be not necessary for binding to the selectin receptors (Review: S. A. Mousa, Drugs of the Future 1996, 21(3), 283).
The course of a number of acute and chronic disorders is unfavorably affected by the excessive adhesion of leucocytes and their infiltration into the tissue. These disorders include, for example, rheumatism, reperfusion injuries such as myocardial ischemia/infarct (MI), acute pneumonia after operative intervention, traumatic shock and stroke, psoriasis, dermatitis, ARDS (adult respiratory distress syndrome) and the restenosis occurring after surgical intervention (for example angioplasty).
A very promising therapeutic starting point is therefore the attempt to employ the tetrasaccharides sLe.sup.X/A in various administration forms or mimetics thereof having a modified structure as antagonists for the modulation or suppression of excessive leucocyte adhesion and to employ them for the alleviation or cure of said disorders.
The natural ligand having the structure of sLe.sup.X has already been successfully used in animal experiments in P-selectin-dependent lung injuries (M. S. Mulligan et al., Nature 1993, 364, 149) and in myocardial reperfusion injuries (M. Buerke et al., J. Clin. Invest. 1994, 93, 1140). In primary clinical trials in acute pneumonia the compound should be employed in a dose of 1 to 2 grams per day per patient (communication of Cytel Corp./La Jolla (Calif.) in the 2nd Glycotechnology Meeting/CHI in La Jolla/U.S.A. on May 16-18th 1994). This high dose of active compound is in agreement with the, as is known, weak affinity of the natural sLe.sup.X/A ligands for the selectin receptors. Thus sLe.sup.X in all known in vitro test systems inhibits cell adhesion to selectin receptors only at a relatively high concentration in the range of IC.sub.50 =1 to 3 mM.
Higher affinity ligands for the selectins have been prepared, which have even more complex structures than sLe.sup.X, higher molecular weights and higher expense with respect to the time and money needed to make substantial amounts of material available (examples are given in Tetrahedron 1995, 51(47), 13015; Angew. Chem. 1996, 108(16), 1949). On the other hand, the mimetics of sLe.sup.X and sLe.sup.A of lower molecular weight thus far described, exhibit equal or lower receptor affinities compared to the natural saccharides (Drugs of the Future 1996, 21(3), 283).